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Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer

Bivalent (poised or paused) chromatin comprises activating and repressing histone modifications at the same location. This combination of epigenetic marks at promoter or enhancer regions keeps genes expressed at low levels but poised for rapid activation. Typically, DNA at bivalent promoters is only...

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Autores principales: Bernhart, Stephan H., Kretzmer, Helene, Holdt, Lesca M., Jühling, Frank, Ammerpohl, Ole, Bergmann, Anke K., Northoff, Bernd H., Doose, Gero, Siebert, Reiner, Stadler, Peter F., Hoffmann, Steve
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120258/
https://www.ncbi.nlm.nih.gov/pubmed/27876760
http://dx.doi.org/10.1038/srep37393
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author Bernhart, Stephan H.
Kretzmer, Helene
Holdt, Lesca M.
Jühling, Frank
Ammerpohl, Ole
Bergmann, Anke K.
Northoff, Bernd H.
Doose, Gero
Siebert, Reiner
Stadler, Peter F.
Hoffmann, Steve
author_facet Bernhart, Stephan H.
Kretzmer, Helene
Holdt, Lesca M.
Jühling, Frank
Ammerpohl, Ole
Bergmann, Anke K.
Northoff, Bernd H.
Doose, Gero
Siebert, Reiner
Stadler, Peter F.
Hoffmann, Steve
author_sort Bernhart, Stephan H.
collection PubMed
description Bivalent (poised or paused) chromatin comprises activating and repressing histone modifications at the same location. This combination of epigenetic marks at promoter or enhancer regions keeps genes expressed at low levels but poised for rapid activation. Typically, DNA at bivalent promoters is only lowly methylated in normal cells, but frequently shows elevated methylation levels in cancer samples. Here, we developed a universal classifier built from chromatin data that can identify cancer samples solely from hypermethylation of bivalent chromatin. Tested on over 7,000 DNA methylation data sets from several cancer types, it reaches an AUC of 0.92. Although higher levels of DNA methylation are often associated with transcriptional silencing, counter-intuitive positive statistical dependencies between DNA methylation and expression levels have been recently reported for two cancer types. Here, we re-analyze combined expression and DNA methylation data sets, comprising over 5,000 samples, and demonstrate that the conjunction of hypermethylation of bivalent chromatin and up-regulation of the corresponding genes is a general phenomenon in cancer. This up-regulation affects many developmental genes and transcription factors, including dozens of homeobox genes and other genes implicated in cancer. Thus, we reason that the disturbance of bivalent chromatin may be intimately linked to tumorigenesis.
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spelling pubmed-51202582016-11-28 Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer Bernhart, Stephan H. Kretzmer, Helene Holdt, Lesca M. Jühling, Frank Ammerpohl, Ole Bergmann, Anke K. Northoff, Bernd H. Doose, Gero Siebert, Reiner Stadler, Peter F. Hoffmann, Steve Sci Rep Article Bivalent (poised or paused) chromatin comprises activating and repressing histone modifications at the same location. This combination of epigenetic marks at promoter or enhancer regions keeps genes expressed at low levels but poised for rapid activation. Typically, DNA at bivalent promoters is only lowly methylated in normal cells, but frequently shows elevated methylation levels in cancer samples. Here, we developed a universal classifier built from chromatin data that can identify cancer samples solely from hypermethylation of bivalent chromatin. Tested on over 7,000 DNA methylation data sets from several cancer types, it reaches an AUC of 0.92. Although higher levels of DNA methylation are often associated with transcriptional silencing, counter-intuitive positive statistical dependencies between DNA methylation and expression levels have been recently reported for two cancer types. Here, we re-analyze combined expression and DNA methylation data sets, comprising over 5,000 samples, and demonstrate that the conjunction of hypermethylation of bivalent chromatin and up-regulation of the corresponding genes is a general phenomenon in cancer. This up-regulation affects many developmental genes and transcription factors, including dozens of homeobox genes and other genes implicated in cancer. Thus, we reason that the disturbance of bivalent chromatin may be intimately linked to tumorigenesis. Nature Publishing Group 2016-11-23 /pmc/articles/PMC5120258/ /pubmed/27876760 http://dx.doi.org/10.1038/srep37393 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Bernhart, Stephan H.
Kretzmer, Helene
Holdt, Lesca M.
Jühling, Frank
Ammerpohl, Ole
Bergmann, Anke K.
Northoff, Bernd H.
Doose, Gero
Siebert, Reiner
Stadler, Peter F.
Hoffmann, Steve
Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer
title Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer
title_full Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer
title_fullStr Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer
title_full_unstemmed Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer
title_short Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer
title_sort changes of bivalent chromatin coincide with increased expression of developmental genes in cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120258/
https://www.ncbi.nlm.nih.gov/pubmed/27876760
http://dx.doi.org/10.1038/srep37393
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